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ALPHABET is a randomized phase III trial assessing alpelisib + trastuzumab with or without fulvestrant in previously treated HER2-positive PIK3CA-mutated advanced breast cancer. Patients will be included in two cohorts according to hormone receptor (HR) status. In the experimental arms, patients in the HR-negative cohort will receive trastuzumab + alpelisib, and patients in the HR-positive cohort will receive the same treatment plus fulvestrant. Patients in the control arms will receive trastuzumab + physician’s choice chemotherapy (eribuline, capecitabine or vinorelbine). Key eligibility criteria include 1–4 previous lines of anti-HER2 therapy and prior trastuzumab emtansine. The primary end point is investigator-assessed progression-free survival. The study aims to recruit a total of 300 patients.

Supplementary Table S1. IC50 values of ipatasertib on cell viability in cell lines with or without alterations in PTEN or PIK3CA. Supplementary Table S2. Percent tumor growth inhibition (%TGI) in xenograft models with or without alterations in PTEN or PIK3CA. Supplementary Table S3. PI3K/Akt pathway status in archival tumors. Supplementary Table S4. Reasons for discontinuation of study. Supplementary Table S5. Common adverse events for ipatasertib in {greater than or equal to} 10% of patients in any presented group. Supplementary Table S6. All Grade {greater than or equal to} 3 adverse events related to ipatasertib. Supplementary Table S7. Hemoglobin A1C (HgbA1C) values for patients who had both pre-treatment and post-treatment values in Stages 1 and 2. Supplementary Table S8. Summary data for patients with best radiographic stable disease (SD) by RECIST version 1.0 criteria. Supplementary Figure S1. Exposure plots confirm that exposures achieved in patients in the dose-escalation stage (right side) correlated with exposures in preclinical models at TGI90 (left side). Supplementary Figure S2. Relationship between exposure of ipatasertib to the most common ipatasertib-related AEs of fatigue, diarrhea, nausea, and rash. Supplementary Figure S3. Suppression of pGSK3β in platelet-rich plasma versus ipatasertib concentrations. Supplementary Figure S4. Pharmacodynamic (PD) dose-dependent elevations in glucose and insulin following treatment with ipatasertib.

Purpose: Aurora A kinase (AAK) is a key regulator of mitosis and a target for anticancer drug development. This phase I study investigated the safety, pharmacokinetics, and pharmacodynamics of MLN8237 (alisertib), an investigational, oral, selective AAK inhibitor, in 59 adults with advanced solid tumors.Experimental Design: Patients received MLN8237 once daily or twice daily for 7, 14, or 21 consecutive days, followed by 14 days recovery, in 21-, 28-, or 35-day cycles. Dose-limiting toxicities (DLT) and the maximum-tolerated dose (MTD) for the 7- and 21-day schedules were determined. Pharmacokinetic parameters were derived from plasma concentration–time profiles. AAK inhibition in skin and tumor biopsies was evaluated and antitumor activity assessed.Results: Neutropenia and stomatitis were the most common DLTs. The MTD for the 7- and 21-day schedules was 50 mg twice daily and 50 mg once daily, respectively. MLN8237 absorption was fast (median time to maximum concentration, 2 hours). Mean terminal half-life was approximately 19 hours. At steady state, pharmacodynamic effects were shown by accumulation of mitotic and apoptotic cells in skin, and exposure-related increases in numbers of mitotic cells with characteristic spindle and chromosomal abnormalities in tumor specimens, supporting AAK inhibition by MLN8237. Stable disease was observed and was durable with repeat treatment cycles, administered over 6 months, in 6 patients, without notable cumulative toxicity.Conclusions: The recommended phase II dose of MLN8237 is 50 mg twice daily on the 7-day schedule, which is being evaluated further in a variety of malignancies, including in a phase III trial in peripheral T-cell lymphoma. Clin Cancer Res; 18(17); 4764–74. ©2012 AACR.

PDF file, 92K, Supplementary Table S1. Summary of pharmacokinetic parameters for MLN8237 once-daily dosing on the 7-day schedule. Supplementary Table S2. Summary of pharmacokinetic parameters for MLN8237 once-daily dosing on the 14-day schedule. Supplementary Table S3. Summary of pharmacokinetic parameters for MLN8237 once-daily dosing on the 21-day schedule. Supplementary Table S4. Summary of pharmacokinetic parameters for MLN8237 twice-daily dosing on the 7-day schedule.

PDF file, 2004K, Figure S2. Changes in skin mitotic index on days 7, 14 and 21.

PDF file, 55K.

Contains supplementary tables and methods

PDF file, 1749K, Figure S4. Changes in tumor mitotic index on days 1, 7, and 21.

PDF file, 2119K, Figure S5. Changes in chromosome alignment and spindle bipolarity on days 1 and 21.

PDF file, 2001K, Figure S3. Changes in skin apoptotic index on days 7, 14 and 21.

Purpose:Addition of alpelisib to fulvestrant significantly extended progression-free survival in PIK3CA-mutant, hormone receptor–positive (HR+) advanced/metastatic breast cancer in the phase III SOLAR-1 study. The combination of alpelisib and letrozole also had promising activity in phase I studies of HR+ advanced/metastatic breast cancer. NEO-ORB aimed to determine whether addition of alpelisib to letrozole could increase response rates in the neoadjuvant setting.Patients and Methods: Postmenopausal women with HR+, human epidermal growth factor receptor 2-negative, T1c-T3 breast cancer were assigned to the PIK3CA-wild-type or PIK3CA-mutant cohort according to their tumor PIK3CA status, and randomized (1:1) to 2.5 mg/day letrozole with 300 mg/day alpelisib or placebo for 24 weeks. Primary endpoints were objective response rate (ORR) and pathologic complete response (pCR) rate for both PIK3CA cohorts.Results:In total, 257 patients were assigned to letrozole plus alpelisib (131 patients) or placebo (126 patients). Grade ≥3 adverse events (≥5% of patients) in the alpelisib arm were hyperglycemia (27%), rash (12%), and maculo-papular rash (8%). The primary objective was not met; ORR in the alpelisib versus placebo arm was 43% versus 45% and 63% versus 61% in the PIK3CA-mutant and wild-type cohorts, respectively. pCR rates were low in all groups. Decreases in Ki-67 were similar across treatment arms and cohorts. In PIK3CA-mutant tumors, alpelisib plus letrozole treatment induced a greater decrease in phosphorylated AKT versus placebo plus letrozole.Conclusions:In contrast to initial results in advanced/metastatic disease, addition of alpelisib to 24-week neoadjuvant letrozole treatment did not improve response in patients with HR+ early breast cancer.

Supplementary methods and results Supplementary Figure 1. Study 1 (NCT01226316) design Supplementary Figure 2. Dose escalation and DLTs in Part A, with MTDs of the continuous, 4/7, and 2/7 schedules being 320, 480, and 640 mg bid, respectively Supplementary Figure 3. Exploratory mutation analyses (ddPCR) in archival tissue and plasma (ctDNA) samples from a breast cancer patient who had progressive disease as best response (Cb cohort) Supplementary Figure 4. A) Tumour growth inhibition in preclinical tumor xenograft models (BT474c, HGC-27, HCC1954 and 786.0) treated with AZD5363 bid po at the indicated doses. B) AZD5363 PD in BT474c tumor xenografts. C) AZD5363 PD at steady state in BT474c xenograft tumors. D) Time course of pPRAS40 and pAkt S473 in BT474c tumor xenograft tissue following the final dose of AZD5363 after 3 weeks' continuous (100 mg/kg bid) or intermittent dosing (130 mg/kg bid 4/7 and 170 mg/kg bid 2/7) Supplementary Figure 5. Glucose (non-fasting/random) values over time after 480 mg single-dose AZD5363 (all dosing schedules) Supplementary Table 1. Percentage change from baseline for PoM biomarkers for 12 evaluable patients Supplementary Table 2. Antibodies and conditions for IHC analysis Supplementary Table 3. ddPCR primers and probes Supplementary Table 4. Tables with results of molecular analyses of Part C patients (PIK3CA and ESR1 mutation status in tissue and ctDNA, PTEN status in archival tissue) Supplementary Table 5. AEs of CTCAE grade {greater than or equal to}3 (irrespective of causality) in Parts A and B (frequency >3% total) and Part C (frequency >5% total)

PDF file, 1635K, Figure S1. MLN8237 dose-escalation and schedule extension schema.

Purpose: This phase I, open-label study (Study 1, D3610C00001; NCT01226316) was the first-in-human evaluation of oral AZD5363, a selective pan-AKT inhibitor, in patients with advanced solid malignancies. The objectives were to investigate the safety, tolerability, and pharmacokinetics of AZD5363, define a recommended dosing schedule, and evaluate preliminary clinical activity.Experimental Design: Patients were aged ≥18 years with World Health Organization (WHO) performance status of 0 to 1. Dose escalation was conducted within separate continuous and intermittent [4 days/week (4/7) or 2 days/week (2/7)] schedules with safety, pharmacokinetic, and pharmacodynamic analyses. Expansion cohorts of approximately 20 patients each explored AZD5363 activity in PIK3CA-mutant breast and gynecologic cancers.Results: MTDs were 320, 480, and 640 mg for continuous (n = 47), 4/7 (n = 21), and 2/7 (n = 22) schedules, respectively. Dose-limiting toxicities were rash and diarrhea for continuous, hyperglycemia for 2/7, and none for 4/7. Common adverse events were diarrhea (78%) and nausea (49%) and, for Common Terminology Criteria for Adverse Events grade ≥3 events, hyperglycemia (20%). The recommended phase II dose (480 mg bid, 4/7 intermittent) was assessed in PIK3CA-mutant breast and gynecologic expansion cohorts: 46% and 56% of patients, respectively, showed a reduction in tumor size, with RECIST responses of 4% and 8%. These responses were less than the prespecified 20% response rate; therefore, the criteria to stop further recruitment to the PIK3CA-mutant cohort were met.Conclusions: At the recommended phase II dose, AZD5363 was well tolerated and achieved plasma levels and robust target modulation in tumors. Proof-of-concept responses were observed in patients with PIK3CA-mutant cancers treated with AZD5363. Clin Cancer Res; 24(9); 2050–9. ©2017 AACR.See related commentary by Costa and Bosch, p. 2029

Biomarkers based on DNA methylation are relevant in the field of environmental health for precision health. Although tobacco smoking is one of the factors with a strong and consistent impact on DNA methylation, there are very few studies analyzing its methylation signature in southern European populations and none examining its modulation by the Mediterranean diet at the epigenome-wide level. We examined blood methylation smoking signatures on the EPIC 850 K array in this population (n = 414 high cardiovascular risk subjects). Epigenome-wide methylation studies (EWASs) were performed analyzing differential methylation CpG sites by smoking status (never, former, and current smokers) and the modulation by adherence to a Mediterranean diet score was explored. Gene-set enrichment analysis was performed for biological and functional interpretation. The predictive value of the top differentially methylated CpGs was analyzed using receiver operative curves. We characterized the DNA methylation signature of smoking in this Mediterranean population by identifying 46 differentially methylated CpGs at the EWAS level in the whole population. The strongest association was observed at the cg21566642 (p = 2.2 × 10−32) in the 2q37.1 region. We also detected other CpGs that have been consistently reported in prior research and discovered some novel differentially methylated CpG sites in subgroup analyses. In addition, we found distinct methylation profiles based on the adherence to the Mediterranean diet. Particularly, we obtained a significant interaction between smoking and diet modulating the cg5575921 methylation in the AHRR gene. In conclusion, we have characterized biomarkers of the methylation signature of tobacco smoking in this population, and suggest that the Mediterranean diet can increase methylation of certain hypomethylated sites.

Endometrial cancer (EC) is the second most common gynecological malignancy worldwide, the first in developed countries [Sung et al. in CA Cancer J Clin 71:209–249, 2021]. Although a majority is diagnosed at an early stage with a low risk of relapse, an important proportion of patients will relapse. Better knowledge of molecular abnormalities is crucial to identify high-risk groups in early stages as well as for recurrent or metastatic disease for whom adjuvant treatment must be personalized. The objective of this guide is to summarize the current evidence for the diagnosis, treatment, and follow-up of EC, and to provide evidence-based recommendations for clinical practice.

Objective. To evaluate the association between surgical timing and postoperative residual disease status on the efficacy of niraparib first-line maintenance therapy in patients with newly diagnosed advanced ovarian can-cer at high risk of recurrence.Methods. Post hoc analysis of the phase 3 PRIMA/ENGOT-OV26/GOG-3012 (NCT02655016) study of niraparib in patients with newly diagnosed primary advanced ovarian, primary peritoneal, or fallopian tube cancer with a complete/partial response to first-line platinum-based chemotherapy. Progression-free survival (PFS) was assessed by surgical status (primary debulking surgery [PDS] vs neoadjuvant chemotherapy/interval debulking surgery [NACT/IDS]) and postoperative residual disease status (no visible residual disease [NVRD] vs visible re-sidual disease [VRD]) in the intent-to-treat population.Results. In PRIMA (N = 733), 236 (32.2%) patients underwent PDS, and 481 (65.6%) received NACT/IDS before enrollment. Median PFS (niraparib vs placebo) and hazard ratios (95% CI) for progression were similar in PDS (13.7 vs 8.2 months; HR, 0.67 [0.47-0.96]) and NACT/IDS (14.2 vs 8.2 months; HR, 0.57 [0.44-0.73]) subgroups. In patients who received NACT/IDS and had NVRD (n = 304), the hazard ratio (95% CI) for progression was 0.65 (0.46-0.91). In patients with VRD following PDS (n = 183) or NACT/IDS (n = 149), the hazard ratios (95% CI) for progression were 0.58 (0.39-0.86) and 0.41 (0.27-0.62), respectively. PFS was not evaluable for patients with PDS and NVRD because of sample size (n = 37).Conclusions. In this post hoc analysis, niraparib efficacy was similar across PDS and NACT/IDS subgroups. Pa-tients who had NACT/IDS and VRD had the highest reduction in the risk of progression with niraparib mainte-nance.(c) 2022 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http:// creativecommons.org/licenses/by-nc-nd/4.0/).

Adenosarcoma; Guidelines; Uterine sarcoma Adenosarcoma; Pautas; Sarcoma uterino Adenosarcoma; Pautes; Sarcoma uterí Uterine sarcomas are very infrequent and heterogeneous entities. Due to its rarity, pathological diagnosis, surgical management, and systemic treatment are challenging. Treatment decision process in these tumors should be taken in a multidisciplinary tumor board. Available evidence is low and, in many cases, based on case series or clinical trials in which these tumors have been included with other soft tissue sarcoma. In these guidelines, we have tried to summarize the most relevant evidence in the diagnosis, staging, pathological disparities, surgical management, systemic treatment, and follow-up of uterine sarcomas.

Background: Paclitaxel is a microtubule-stabilizing chemotherapeutic agent. Despite its widespread use, it damages healthy tissues such as skin. The goal of this study was to prove that the real impact of paclitaxel-induced skin toxicity could be underestimated because the adverse events might appear asymptomatic. Methods: Gynecological cancer patients were recruited. Skin parameters measurements were taken after three and six paclitaxel cycles. Measurements were conducted using specific probes which measure hydration, transepidermal water loss (TEWL), sebum, elasticity and firmness, erythema, roughness, smoothness, skin thickness, and desquamation levels. Further, a 3D epidermis model was incubated with paclitaxel to analyze gene and protein expression of aquaporin 3, collagen type 1, elastin, and fibronectin. Results: Paclitaxel induced alterations in the skin parameters with no visible clinical manifestations. Gynecological cancer patients under paclitaxel treatment had a decrease in hydration, TEWL, sebum, elasticity, and thickness of the skin, while erythema, roughness, and desquamation were increased. The molecular markers, related to hydration and the support of the skin layers, and analyzed in the 3D epidermis model, were decreased. Conclusions: Results suggest that paclitaxel modifies gene and protein expression of skin-related molecular markers, and impairs different physical, physiological, and biomechanical properties of the skin of cancer patients at a subclinical level. This work was supported by the grants PID2020-114871RB-I00 (JC), European Regional Development Fund (FEDER), and Instituto de Salud Carlos III, PI20/01363 (JM), CIBERES (CB06/06/0027) from the Spanish Government, and by research grants from the Regional Government Prometeo 2017/023/UV (JC), from “Generalitat Valenciana”. Funding entities did not contribute to the study design or data collection, analysis, and interpretation, or to the writing of the manuscript.

Background Xentuzumab—a humanised IgG1 monoclonal antibody—binds IGF-1 and IGF-2, inhibiting their growth-promoting signalling and suppressing AKT activation by everolimus. This phase Ib/II exploratory trial evaluated xentuzumab plus everolimus and exemestane in hormone receptor-positive, locally advanced and/or metastatic breast cancer (LA/MBC). Methods Patients with hormone receptor-positive/HER2-negative LA/MBC resistant to non-steroidal aromatase inhibitors were enrolled. Maximum tolerated dose (MTD) and recommended phase II dose (RP2D) of xentuzumab/everolimus/exemestane were determined in phase I (single-arm, dose-escalation). In phase II (open-label), patients were randomised 1:1 to the RP2D of xentuzumab/everolimus/exemestane or everolimus/exemestane alone. Randomisation was stratified by the presence of visceral metastases. Primary endpoint was progression-free survival (PFS). Results MTD was determined as xentuzumab 1000 mg weekly plus everolimus 10 mg/day and exemestane 25 mg/day. A total of 140 patients were enrolled in phase II (70 to each arm). Further recruitment was stopped following an unfavourable benefit-risk assessment by the internal Data Monitoring Committee appointed by the sponsor. Xentuzumab was discontinued; patients could receive everolimus/exemestane if clinically indicated. Median PFS was 7.3 months (95% CI 3.3–not calculable) in the xentuzumab/everolimus/exemestane group and 5.6 months (3.7–9.1) in the everolimus/exemestane group (hazard ratio 0.97, 95% CI 0.57–1.65; P = 0.9057). In a pre-specified subgroup of patients without visceral metastases at screening, xentuzumab/everolimus/exemestane showed evidence of PFS benefit versus everolimus/exemestane (hazard ratio 0.21 [0.05–0.98]; P = 0.0293). Most common any-cause adverse events in phase II were diarrhoea (29 [41.4%] in the xentuzumab/everolimus/exemestane group versus 20 [29.0%] in the everolimus/exemestane group), mucosal inflammation (27 [38.6%] versus 21 [30.4%]), stomatitis (24 [34.3%] versus 24 [34.8%]), and asthenia (21 [30.0%] versus 24 [34.8%]). Conclusions Addition of xentuzumab to everolimus/exemestane did not improve PFS in the overall population, leading to early discontinuation of the trial. Evidence of PFS benefit was observed in patients without visceral metastases when treated with xentuzumab/everolimus/exemestane, leading to initiation of the phase II XENERA™-1 trial (NCT03659136). Trial registration ClinicalTrials.gov, NCT02123823. Prospectively registered, 8 March 2013.

Delayed-type hypersensitivity (DTH) is caused by a broad number of drugs used in clinic, and antineoplastic drugs show an elevated proportion of DTH, which potentially affects the quality of life of patients. Despite the serious problem and the negative economic impact deriving from market withdrawal of such drugs and high hospitalization costs, nowadays, there are no standard validated methods in vitro or in vivo to evaluate the sensitizing potential of drugs in the preclinical phase. Enhanced predictions in preclinical safety evaluations are really important, and for that reason, the aim of our work is to adapt in vitro DPRA, ARE-Nrf2 luciferase KeratinoSensTM, and hCLAT assays for the study of the sensitizing potential of antineoplastic agents grouped by mechanism of action. Our results reveal that the above tests are in vitro techniques able to predict the sensitizing potential of the tested antineoplastics. Moreover, this is the first time that the inhibition of the VEGFR1 pathway has been identified as a potential trigger of DTH.

BACKGROUND: Young breast cancer (BC) survivors are at risk of infertility. Ovarian stimulation for fertility preservation before (neo)adjuvant chemotherapy is standard of care. Research efforts have shown no negative prognostic effect of pregnancy following BC therapy, also among BRCA carriers. Currently, poor evidence is available on the safety to undergo ART following BC treatment, with no data in carriers of germline BRCA pathogenic variants. To provide evidence on the safety of fertility treatments in this specific population, we assessed the outcomes of a cohort of BRCA-mutated BC survivors who had a pregnancy after prior BC history by comparing the group of patients who underwent ART to achieve pregnancy to the group with spontaneous pregnancy. METHODS: We conducted a multicenter retrospective cohort study across 30 centers worldwide including women diagnosed at ≤ 40 years with stage I-III BC, between January 2000 and December 2012, bearing germline BRCA1/2 pathogenic variants. Survivors with a pregnancy (any outcome) after BC, with no disease-free survival (DFS) event before pregnancy, were assigned to the ART and non-ART group if their pregnancy was achieved through ART or spontaneously, respectively. ART procedures included ovulation induction, ovarian stimulation for in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI), and embryo transfer under hormonal replacement therapy (HRT). RESULTS: Of 1,424 patients registered in the study, 168 with a pregnancy after BC were included in the present analysis. A total of 22 patients were included in the ART group and 146 in the non-ART group. Before BC diagnosis, 18.2% patients in the ART group had at least one child, compared to 38.4% in the non-ART group (P=0.030). Patients had a median age at BC diagnosis of 33.0 vs 30.2 years old in the ART group and in the non-ART group, respectively (P=0.004); 45.4% and 17.1% had grade 1-2 tumors, respectively (P=0.008), and 59.1% vs 31.5% had hormone receptor-positive tumors, respectively (P=0.016). Both cohorts had similar tumor size and nodal stage characteristics. Type and duration of endocrine therapy were comparable between groups. The type of ART was not specified in 5 survivors (22.7%). Ovulation induction was used in 1 patient (4.5%), ovarian stimulation in 7 patients (31.8%), embryo transfer under HRT following oocyte donation in 5 patients (22.7%), and embryo transfer under HRT following oocyte and/or embryo cryopreservation for fertility preservation in 4 patients (18.2%). Median age at conception among survivors was 39.7 years in the ART group versus 35.4 years in the non-ART group (P Citation Format: Margherita Condorelli, Marco Bruzzone, Marcello Ceppi, Alberta Ferrari, Albert Grinshpun, Anne-Sophie Hamy, Evandro de Azambuja, Estela Carrasco, Fedro A. Peccatori, Antonio Di Meglio, Shani Paluch-Shimon, Philip D. Poorvu, Marta Venturelli, Christine Rousset-Jablonski, Claire Senechal, Luca Livraghi, Riccardo Ponzone, Laura De Marchis, Katarzyna Pogoda, Amir Sonnenblick, Cynthia Villarreal-Garza, Octavi Córdoba, Luis Teixeira, Florian Clatot, Kevin Punie, Rossella Graffeo Galbiati, Maria Vittoria Dieci, Alejandro Pérez-Fidalgo, Francois P. Duhoux, Fabio Puglisi, Arlindo R. Ferreira, Eva Blondeaux, Tamar Peretz-Yablonski, Olivier Caron, Claire Saule, Lieveke Ameye, Judith Balmaña, Ann H. Partridge, Hatem A. Azim, Jr, Isabelle Demeestere, Matteo Lambertini. Safety of assisted reproductive technologies (ART) following treatment completion in young women with germline BRCA pathogenic variants having a pregnancy after breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr PD5-06.

Purpose This multicenter phase II trial evaluated lurbinectedin (PM01183), a selective inhibitor of active transcription of protein-coding genes, in patients with metastatic breast cancer. A unicenter translational substudy assessed potential mechanisms of lurbinectedin resistance. Patients and Methods Two arms were evaluated according to germline BRCA1/2 status: BRCA1/2 mutated (arm A; n = 54) and unselected ( BRCA1/2 wild-type or unknown status; arm B; n = 35). Lurbinectedin starting dose was a 7-mg flat dose and later, 3.5 mg/m2 in arm A. The primary end point was objective response rate (ORR) per Response Evaluation Criteria in Solid Tumors (RECIST). The translational substudy of resistance mechanisms included exome sequencing (n = 13) and in vivo experiments with patient-derived xenografts (n = 11) from BRCA1/2-mutated tumors. Results ORR was 41% (95% CI, 28% to 55%) in arm A and 9% (95% CI, 2% to 24%) in arm B. In arm A, median progression-free survival was 4.6 months (95% CI, 3.0 to 6.0 months), and median overall survival was 20.0 months (95% CI, 11.8 to 26.6 months). Patients with BRCA2 mutations showed an ORR of 61%, median progression-free survival of 5.9 months, and median overall survival of 26.6 months. The safety profile improved with lurbinectedin dose adjustment to body surface area. The most common nonhematologic adverse events seen at 3.5 mg/m2 were nausea (74%; grade 3, 5%) and fatigue (74%; grade 3, 21%). Neutropenia was the most common severe hematologic adverse event (grade 3, 47%; grade 4, 10%). Exome sequencing showed mutations in genes related to the nucleotide excision repair pathway in four of seven tumors at primary or acquired resistance and in one patient with short-term stable disease. In vivo, sensitivity to cisplatin and lurbinectedin was evidenced in lurbinectedin-resistant (one of two) and cisplatin-resistant (two of three) patient-derived xenografts. Conclusion Lurbinectedin showed noteworthy activity in patients with BRCA1/2 mutations. Response and survival was notable in those with BRCA2 mutations. Additional clinical development in this subset of patients with metastatic breast cancer is warranted.

Background Resistance to endocrine treatment in metastatic breast cancer is a major clinical challenge. Clinical tools to predict both drug resistance and possible treatment combination approaches to overcome it are lacking. This unmet need is mainly due to the heterogeneity underlying both the mechanisms involved in resistance development and breast cancer itself. Methods To study the complexity of the mechanisms involved in the resistance to the selective estrogen receptor degrader (SERD) fulvestrant, we performed comprehensive biomarker analyses using several in vitro models that recapitulate the heterogeneity of developed resistance. We further corroborated our findings in tissue samples from patients treated with fulvestrant. Results We found that different in vitro models of fulvestrant resistance show variable stability in their phenotypes, which corresponded with distinct genomic alterations. Notably, the studied models presented adaptation at different cell cycle nodes to facilitate progression through the cell cycle and responded differently to CDK inhibitors. Cyclin E2 overexpression was identified as a biomarker of a persistent fulvestrant-resistant phenotype. Comparison of pre- and post-treatment paired tumor biopsies from patients treated with fulvestrant revealed an upregulation of cyclin E2 upon development of resistance. Moreover, overexpression of this cyclin was found to be a prognostic factor determining resistance to fulvestrant and shorter progression-free survival. Conclusions These data highlight the complexity of estrogen receptor positive breast cancer and suggest that the development of diverse resistance mechanisms dictate levels of ER independence and potentially cross-resistance to CDK inhibitors.

Additional file 1. : Supplementary material. Supplementary methods, tables and figure

Introduction Molecular-matched therapies have revolutionized cancer treatment. We evaluated the improvement in clinical outcomes of applying an in-house customized Next Generation Sequencing panel in a single institution. Methods Patients with advanced solid tumors were molecularly selected to receive a molecular-matched treatment into early phase clinical trials versus best investigators choice, according to the evaluation of a multidisciplinary molecular tumor board. The primary endpoint was progression-free survival (PFS) assessed by the ratio of patients presenting 1.3-fold longer PFS on matched therapy (PFS2) than with prior therapy (PFS1). Results Of a total of 231 molecularly screened patients, 87 were eligible for analysis. Patients who received matched therapy had a higher median PFS2 (6.47 months; 95% CI, 2.24–14.43) compared to those who received standard therapy (2.76 months; 95% CI, 2.14–3.91, Log-rank p = 0.022). The proportion of patients with a PFS2/PFS1 ratio over 1.3 was significantly higher in the experimental arm (0.33 vs 0.08; p = 0.008). Discussion We demonstrate the pivotal role of the institutional molecular tumor board in evaluating the results of a customized NGS panel. This process optimizes the selection of available therapies, improving disease control. Prospective randomized trials are needed to confirm this approach and open the door to expanded drug access.

Simple Summary This is a collaborative approach between two multicentre structures, the Spanish Group of Ovarian Cancer Research (GEICO) and the Spanish Biobank Network (RNBB), for collecting high-quality clinical data and associated biospecimens from gynaecological patients in the context of a virtual clinical registry (VCR). The model described herein defines the mode of operation of this initiative and represents a win-win example between multicentre structures that will contribute to the success of translational research in gynaecological cancer. As of December 2021, 30 active sites have recruited a total of 655 patients in the GEICO VCR, distributed in the following cohorts: Ovarian Cancer (377), Endometrial Cancer (206), Cervical Cancer (67), and Rare Tumours (5). The main type of associated biospecimens are formalin-fixed and paraffin-embedded tissue, plasma, serum, and buffy-coat. Patient registries linked to biorepositories constitute a valuable asset for clinical and translational research in oncology. The Spanish Group of Ovarian Cancer Research (GEICO), in collaboration with the Spanish Biobank Network (RNBB), has developed a multicentre, multistakeholder, prospective virtual clinical registry (VCR) associated with biobanks for the collection of real-world data and biological samples of gynaecological cancer patients. This collaborative project aims to promote research by providing broad access to high-quality clinical data and biospecimens for future research according to the needs of investigators and to increase diagnostic and therapeutic opportunities for gynaecological cancer patients in Spain. The VCR will include the participation of more than 60 Spanish hospitals entering relevant clinical information in harmonised electronic case report forms (eCRFs) in four different cohorts: ovarian, endometrial, cervical, and rare gynaecological cancers (gestational trophoblastic disease). Initial data for the cases included till December 2021 are presented. The model described herein establishes a real-world win-win collaboration between multicentre structures, promoted and supported by GEICO, that will contribute to the success of translational research in gynaecological cancer.

Aurora kinases (AURK) are key regulators of the mitotic spindle formation. AURK is frequently overexpressed in ovarian cancer and this overexpression has been frequently associated with prognosis in these tumours. Interestingly, AURK have been shown to interact with DNA repair mechanisms and other cell cycle regulators. These functions have brought light to Aurora family as a potential target for anticancer therapy. In the last years, two clinical trials with different AURK inhibitors have shown activity in epithelial and clear-cell ovarian cancer. Although there is a lack of predictive factors of AURK inhibition activity, recent trials have identified some candidates. This review will focus in the functions of the AURK family, its role as prognostic factor in epithelial ovarian cancer and potential clinical implications.

Young women with germlineThis is an international, multicenter, hospital-based, retrospective cohort study. Eligible patients were diagnosed between January 2000 and December 2012 with invasive early breast cancer at age ≤ 40 years and harbored deleterious germlineOf 1,252 patients with germlinePregnancy after breast cancer in patients with germline

Advances in the understanding of the histological and molecular characteristics of ovarian cancer now allow 5subtypes to be identified, leading to a more refined therapeutic approach and improved clinical trials. Each of the subtypes has specific histological features and a particular biomarker expression, as well as mutations in different genes, some of which have prognostic and predictive value. CA125 and HE4 are examples of ovarian cancer biomarkers used in diagnosis and follow-up. Currently, somatic or germinal mutations on BRCA1 and BRCA2 genes are the most important biomarkers in epithelial ovarian cancer, having prognostic and predictive value. In this article, a group of experts from the Spanish Society of Medical Oncology and the Spanish Society of Pathology review the histological and molecular characteristics of the 5subtypes of ovarian cancer and describe the most useful biomarkers and mutations for diagnosis, screening and tailored treatment strategy.

Purpose: This study aimed to identify biomarkers of resistance to endocrine therapy in estrogen receptor–positive (ER+) breast cancers treated with prolonged neoadjuvant letrozole.Experimental Design: We performed targeted DNA and RNA sequencing in 68 ER+ breast cancers from patients treated with preoperative letrozole (median, 7 months).Results: Twenty-four tumors (35%) exhibited a PEPI score ≥4 and/or recurred after a median of 58 months and were considered endocrine resistant. Integration of the 47 most upregulated genes (log FC > 1, FDR < 0.03) in letrozole-resistant tumors with transcription-binding data showed significant overlap with 20 E2F4-regulated genes (P = 2.56E−15). In patients treated with the CDK4/6 inhibitor palbociclib before surgery, treatment significantly decreased expression of 24 of the 47 most upregulated genes in letrozole-resistant tumors, including 18 of the 20 E2F4 target genes. In long-term estrogen-deprived ER+ breast cancer cells, palbociclib also downregulated all 20 E2F4 target genes and P-RB levels, whereas the ER downregulator fulvestrant or paclitaxel only partially suppressed expression of this set of genes and had no effect on P-RB. Finally, an E2F4 activation signature was strongly associated with resistance to aromatase inhibitors in the ACOSOG Z1031B neoadjuvant trial and with an increased risk of relapse in adjuvant-treated ER+ tumors in METABRIC.Conclusions: In tumors resistant to prolonged neoadjuvant letrozole, we identified a gene expression signature of E2F4 target activation. CDK4/6 inhibition suppressed E2F4 target gene expression in estrogen-deprived ER+ breast cancer cells and in patients' ER+ tumors, suggesting a potential benefit of adjuvant CDK4/6 inhibitors in patients with ER+ breast cancer who fail to respond to preoperative estrogen deprivation. Clin Cancer Res; 24(11); 2517–29. ©2018 AACR.

Background: Breast cancer (BC) is a heterogeneous disease. HER2+ BC represents between 15-20% of cases. Trastuzumab, a monoclonal antibody, has been successfully improved clinical benefits in both localized and advanced setting. Despite this evidence, many patients experience resistance to therapy. The objective of this study is to analyze AXL receptor as a potential mechanism of resistance and its implication as a prognostic factor. Methods: We used three breast cancer cell lines with acquired resistance to Trastuzumab. Resistant models were generated by treating parental cells (AU565, SKR3, BT474) with constant dose of Trastuzumab (15μg/mL) for 6 months. Cell viability was estimated by MTT assay. Proteins were assessed by Western blot and genes by qRT-PCR. AXL was downregulated by siRNA and a selective tyrosine kinase (TK) AXL inhibitor (TP-0903). Proteins interaction was assessed by immunoprecipitation and Duolink®PLA. The prognostic value of AXL was evaluated in primary tumor in a cohort of HER2+ BC patients treated with Trastuzumab plus chemotherapy from our center (n=33). Results: Acquired resistant cell lines (RCLs) maintained HER2 amplification. RCLs were more proliferative than sensitive parental cell lines. There was an important up-regulation of AXL (>2.5 fold-change) and epithelial-mesenchymal transition markers (VIM, CDH2, CTNNB1 and FN1) in RCLs (p Citation Format: Anna Adam-Artigues, Eduardo Tormo, Raimundo Cervera, Federico Rojo, Alejandro Pérez-Fidalgo, Sandra Zazo, Paula González-Alonso, Cristina Hernándo, María Teresa Martínez, Valentina Gambardella, Jesús Poveda, Soraya Simón, Belén Ortega, Santiago Moragón, Ana Rovira, Joan Albanell, Octavio Burgués, Begoña Bermejo, Pilar Eroles, Ana Lluch, Juan Miguel Cejalvo. AXL-HER2 dimer as mechanism of anti-HER2 acquired resistance in HER2 amplified brest cancer models: A new step towards precision medicine [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P6-03-05.

Leptin is a hormone crucial in the regulation of food intake and body-weight maintenance. However, the genes and gene variants that influence its plasma levels are still not well known. Results of studies investigating polymorphisms in candidate genes have been inconsistent, and, in addition, very few genome-wide association studies (GWAS) have been undertaken. Our aim was to investigate the genes and gene variants most associated with plasma leptin concentrations in a high-cardiovascular-risk Mediterranean population. We measured plasma leptin in 1011 men and women, and analyzed the genetic factors associated using three approaches: (1) Analyzing the single nucleotide polymorphisms (SNPs) reported in a GWAS meta-analysis in other populations (including an SNP in/near each of these LEP, SLC32A1, GCKR, CCNL, COBLL1, and FTO genes), (2) Investigating additional SNPs in/near those genes, also including the RLEP gene, and (3) Undertaking a GWAS to discover new genes. We did not find any statistically significant associations between the previously published SNPs and plasma leptin (Ln) in the whole population adjusting for sex and age. However, on undertaking an extensive screening of other gene variants in those genes to capture a more complete set of SNPs, we found more associations. Outstanding among the findings was the heterogeneity per sex. We detected several statistically significant interaction terms with sex for these SNPs in the candidate genes. The gene most associated with plasma leptin levels was the FTO gene in men (specifically the rs1075440 SNP) and the LEPR in women (specifically the rs12145690 SNP). In the GWAS on the whole population, we found several new associations at the p &lt, 1 &times, 10&minus, 5 level, among them with the rs245908-CHN2 SNP (p = 1.6 &times, 6). We also detected a SNP*sex interaction at the GWAS significance level (p &lt, 5 &times, 8), involving the SLIT3 gene, a gene regulated by estrogens. In conclusion, our study shows that the SNPs selected as relevant for plasma leptin levels in other populations, are not good markers for this Mediterranean population, so supporting those studies claiming a bias when generalizing GWAS results to different populations. These population-specific differences may include not only genetic characteristics, but also age, health status, and the influence of other environmental variables. In addition, we have detected several sex-specific effects. These results suggest that genomic analyses, involving leptin, should be estimated by sex and consider population-specificity for more precise estimations.

PURPOSE: To determine the maximum tolerated dose (MTD) of BEZ235, an oral inhibitor of class I PI3K and mTOR complexes 1 and 2. METHODS: We performed a phase I/Ib, multicenter, open-label study of oral BEZ235 administered in a continuous daily schedule. The study consisted of two parts: dose-escalation part and safety-expansion part. BEZ235 was administered as a single agent to patients with solid tumors or in combination with trastuzumab for HER2+ advanced breast cancer (aBC). Primary end points were MTD, safety, and tolerability. The secondary end point was pharmacokinetics. Other formulations of BEZ235, solid dispersion system (SDS) sachet, and SDS capsules were also assessed. RESULTS: One hundred and eighty-three patients were enrolled; single-agent BEZ235 was administered as hard gelatin capsule (n = 59), SDS capsules A and B (n = 33), and SDS sachet (n = 61), amongst which SDS sachet was chosen as the preferred formulation. The monotherapy MTD for capsule A and SDS sachet was determined to be 1000 and 1200 mg/day, respectively. Thirty patients with HER2+ aBC received BEZ235 in combination with trastuzumab. The MTD of BEZ235 in combination with trastuzumab was 600 mg/day. A total of four patients (13.3%) achieved partial response across the different groups. Most frequent AEs in single agent and combination cohorts included nausea (80.3 and 93.3%), diarrhea (75.4 and 80.0%), and vomiting (63.9 and 63.3%). CONCLUSIONS: The MTD of BEZ235 as single agent was 1200 and 600 mg/day with trastuzumab. Pharmacokinetic profiles showed low-to-moderate variability at low dose (10 mg) and high variability at high doses (100 mg and above). Gastrointestinal AEs were frequent at high doses.

Background: Metastatic breast cancer (MBC) is a clinically heterogeneous disease in which selective approaches are needed to identify patients (pts) who will benefit the most from available therapies and avoid unnecessary toxicities. Lurbinectedin (PM01183) is a new anticancer drug that binds to the DNA minor groove inducing double-strand breaks and blocking transcription. It has significant in vitro and in vivo antitumor activity, particularly in breast cancer models. PM01183 is more active against homologous recombination-deficient cell lines. Hence, MBC pts with deleterious germline BRCA mutations might be more sensitive to PM01183 than those with sporadic tumors. PM1183 activity was shown in different tumor types in clinical trials, especially in pts with platinum-resistant ovarian cancer (objective response rate [ORR]: 30%). Methods: MBC pts < 75-years-old with ductal or lobular carcinoma pretreated with ≤ 3 chemotherapy regimens for MBC, measurable disease per RECIST v1.1, performance status (PS) ≤1 and adequate major organ function are being treated with PM01183 7.0 mg flat dose i.v. every 3 weeks. The primary aim is to evaluate the clinical efficacy of PM01183 in two cohorts of MBC pts: cohort A: BRCA+ (known germline BRCA1/2 mutation) and cohort B: unselected (BRCA1/2 wild type or unknown mutation status). The primary endpoint is confirmed ORR by RECIST v1.1. A futility analysis was planned when 20 and 30 pts were recruited in cohort A and B, respectively. If at least 4 pts in cohort A and 3 pts in cohort B, achieve a response, recruitment in that cohort will continue up to 53 and 64 total pts, respectively. Results: As of June 2014, 56 pts had been enrolled. Cohort A/B (n: 21/35): Median age 40/52-years-old; Cohort A(%)/B(%): PS 0: 48/66; >2 metastatic sites: 58/40; most common sites of metastasis: lymph node 79/33, liver 48/60 and bone 42/48; triple negative: 57/46; hormonal receptor +: 38/49; prior anthracyclines: 95/91, taxanes: 100/94, platinum: 52/26, PARPi: 29/0; cohort A: BRCA 1/2 (%): 52/48. Cohort A-BRCA 1/2+ (n=21)Cohort B-unselected (n=35)Median cycles (range)4 (1-20)3 (1-14)Best overall response(n= 17 evaluable)(n= 34 evaluable)CR1 (6%)0PR6 (35%)3 (9%)SD6 (35%)16 (47%)PD4 (24%)15 (44%)ORR (95%CI)41% (18-67%)9% (1.9-23.7%)Median duration of response Monts (95%CI)5.0 (0.1-12.8)3.3 (1.4-5.1) In an exploratory analysis, ORR in cohort A was higher in PARPi naïve pts: 64% (7/11 pts). Grade (G) 3-4 related adverse events occurred in >5% pts were myelosuppression (neutropenia 69%, febrile neutropenia 7%, thrombocytopenia 14%); G3 fatigue 7%, transient transaminase increase 19% (G4: 2%), nausea 6% and dyspnea 6% (3 pts, 2 of them due to pneumonitis). One patient with massive liver involvement and impaired function died on C1D4 due to multiorgan failure possibly related to the study drug. Conclusions: PM01183 has promising activity in pretreated MBC pts with BRCA mutation. Safety profile appears to be mostly predictable and with non-cumulative toxicity. Treatment-related neutropenia was manageable with G-CSF and/or dose reduction. After futility analysis, targeted activity has been met in cohort A (BRCA+), and recruitment will continue up to 53 evaluable BRCA+ pts. Citation Format: Judit Balmaña, Cristina Cruz, Judy Garber, Jose A Perez Fidalgo, Ana Lluch, Nadine Tung, Silvia Antolin, Cristian Fernandez, Carmen Kahatt, Sergio Szyldergemajn, Arturo Soto Matos, Sonia Extremera, Jose Baselga, Steven J Isakoff. Lurbinectedin (PM01183) activity in BRCA1/2-associated or unselected metastatic breast cancer. Interim results of an ongoing phase II trial [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P3-13-01.

Resumen El cancer de mama HER2 positivo supone aproximadamente un 15% de los tumores malignos de mama. La terapia anti-HER2, principalmente representada por trastuzumab, es el pilar del tratamiento de esta enfermedad. La prolongacion en la supervivencia que han conseguido las nuevas terapias anti-HER2, y el tratamiento dilatado de estas pacientes en los estadios precoces de la enfermedad asi como en la enfermedad avanzada, supone un importante reto a los recursos existentes, tanto con respecto al personal sanitario y el tiempo de los hospitales de dia oncologicos, como en cuanto al tiempo dedicado por las pacientes para su tratamiento. El desarrollo de una formulacion subcutanea ha supuesto una disminucion significativa en la utilizacion de estos recursos y facilidad de uso. En esta revision, presentamos el desarrollo de esta nueva formulacion, asi como los datos de eficacia y preferencia.

Resumen Introduccion El cancer oculto de mama (COM), con una incidencia del 0,3-1%, aun plantea retos diagnosticos y terapeuticos. El objetivo del trabajo fue determinar las caracteristicas patologicas de nuestra serie de COM, evaluar los resultados de las tecnicas diagnosticas y terapeuticas empleadas (cirugia mamaria con linfadenectomia axilar o solo linfadenectomia axilar) y la supervivencia global. Pacientes y metodos Analisis retrospectivo de 21 pacientes con metastasis ganglionares de cancer mamario con mamografia y ecografia mamaria negativas. Desde 2003 se incluyo la resonancia magnetica nuclear (RMN) en el protocolo de estudio. Se valoro la supervivencia en 2 grupos; grupo A: pacientes con COM tratadas con cirugia mamaria (15 casos), bien mastectomia radical (10 pacientes) bien cirugia conservadora (5 casos), y grupo B: 4 pacientes tratadas quirurgicamente con linfadenectomia axilar niveles i y ii de Berg. Se asocio radioterapia sobre la mama tras cirugia conservadora (50 Gy) y sobre la axila si > 3 adenopatias axilares tumorales. Resultados En 9 pacientes (7 de las mastectomias y 2 de las cirugias conservadoras) se identifico histologicamente un carcinoma de mama, de tipo ductal infiltrante en 8 casos y un carcinoma medular. La RMN (6 casos) demostro en 2 pacientes tumor mamario con confirmacion histologica de carcinoma. Con una mediana de seguimiento de 87 meses, la supervivencia global fue de 101,2 meses (rango: 12-235 meses) con una supervivencia a 5 anos del 69%. La supervivencia media en el grupo A fue de 120 meses, superior a los 41 meses del grupo B (p = 0,05). Conclusiones En nuestra serie el tratamiento quirurgico sobre la mama mejora la supervivencia global respecto al grupo tratado solo con linfadenectomia axilar. La RMN ha sido util para evidenciar nodulos tumorales ante un supuesto COM y permite seleccionar a pacientes para realizar cirugia conservadora de la mama.